This invention relates to the fields of pharmaceutical and organic chemistry and provides novel inclusion complexes, and pharmaceutical formulations thereof, which are useful for the treatment of certain medical indications in mammals.
Benzothiophenes of formula I ##STR1## wherein
R.sup.1 and R.sup.3 each are independently hydrogen, C.sub.1 -C.sub.4 alkyl, --CO--(C.sub.1 -C.sub.6 alkyl), or --CO--Ar in which Ar is optionally substituted phenyl; and
R.sup.2 is selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino; or a salt thereof, are well known in the art (see, e.g., U.S. Pat. No. 4,133,814). These compounds are known to be effective for the treatment of a variety of mammalian, particularly human, medical indications including, for example, postmenopausal osteoporosis and high serum cholesterol [see, e.g., Draper, et al., Effects of Raloxifene (LY139481 HCl) on Biochemical Markers of Bone and Lipid Metabolism in Healthy Postmenopausal Women, and Bryant, et al., Protection from Bone Loss and Lowering of Serum Cholesterol in the Absence of Uterin Stimulation in Overiectomized Rats, Am. Soc. Bone and Min. Res., Tampa, 9/18-22/93].
Compounds of formula I, and particularly acid salt forms of such compounds including, for example, hydrochloride, sulfate, hydrobromide, titrate, and the like, generally are poorly water soluble under ambient temperature. Because of this poor water solubility, it presently is necessary to administer these compounds as a suspension in water using a suspending agent such as carboxymethyl cellulose (CMC), polyethylene glycol, and the like. However, the present pharmaceutical formulations used with compounds of formula I cannot be utilized for many methods of administration.
Particularly, formulations useful for intravenous (IV) administration must be in the form of a solution. The IV administration of a suspension is extremely dangerous because particulate material in suspension can lodge in the microvasculature of a mammal causing life-threatening blockages and embolisms.
Water soluble formulations also are necessary for intranasal and aerosol administration of pharmaceutical agents because water solubility is necessary for such agents to cross upper and lower respiratory tract membranes. Failure to provide water soluble forms of these agents generally leads to poor drug absorption and/or irritation of the respiratory tract.
Additionally, it is desirable, although less critical, to have water soluble formulations available for other routes of administration. For example, liquid formulations for oral administration are desirable because they are more homogenous than other forms of pharmaceutical agents, and therefore, provide better dispersion and absorption in the GI tract. A water soluble formulation of a pharmaceutical agent also provides greater safety and convenience for a patient and the attending physician.
Although previous attempts of solubilizing compounds of formula I for use in pharmaceutical formulations generally have failed, the present invention provides novel aqueous solution inclusion complexes, pharmaceutical compositions thereof, and methods of using such complexes.